The goal of this revised Phase 1 proposal remains to identify and initiate the pharmaceutical development of a topical formulation ingredient capable of reducing the risk associated with dermal and systemic exposure to hazardous materials (i.e., a permeation retarder). The strategy is to select a lead chemical entity from several candidate molecules designed to interact with the stratum comeum so that it becomes less permeable to toxic agents. The selection of an effective skin permeation retarder will be based upon its ability to reduce the skin absorption of a variety of hazardous materials, be substantive to skin such that it will be active for prolonged periods of time, and show essentially no dermal toxicity. In Phase I of this project we intend to synthesize and evaluate in vitro the permeation retardant efficacy of several potential retarder candidates, perform primary dermal and acute oral toxicity analysis in animals of a lead and back-up candidate, and perform formulation studies that will generate prototype products. In Phase II we will seek to scale-up the synthesis of the lead compound, optimize potential formulations, determine long-term chemical, microbiological and physical stability, and complete safety and efficacy studies as required by the FDA. PROPOSED COMMERCIAL APPLICATION: The $20 B personal care product market covers a collection of diverse products, most of which involve contact with the skin. Many of the ingredients of such products are irritants or sensitizers and some may be systemically toxic. A general ingredient that will reduce the skin absorption of such materials should find widespread use in this market. In addition, an effective skin barrier formulation might also find use in pharmaceutical, occupational, military and household environments.